| 1. |
- Lienard, Julia, et al.
(författare)
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ESX-1 exploits type I IFN-signalling to promote a regulatory macrophage phenotype refractory to IFNγ-mediated autophagy and growth restriction of intracellular mycobacteria
- 2016
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Ingår i: Cellular Microbiology. - : Hindawi Limited. - 1462-5814. ; 18:10, s. 1471-1485
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Tidskriftsartikel (refereegranskat)abstract
- Summary: The ability of macrophages to eradicate intracellular pathogens is normally greatly enhanced by IFNγ, a cytokine produced mainly after onset of adaptive immunity. However, adaptive immunity is unable to provide sterilizing immunity against mycobacteria, suggesting that mycobacteria have evolved virulence strategies to inhibit the bactericidal effect of IFNγ-signalling in macrophages. Still, the host-pathogen interactions and cellular mechanisms responsible for this feature have remained elusive. We demonstrate that the ESX-1 type VII secretion systems of Mycobacterium tuberculosis and Mycobacteriummarinum exploit type I IFN-signalling to promote an IL-12low/IL-10high regulatory macrophage phenotype characterized by secretion of IL-10, IL-27 and IL-6. This mechanism had no impact on intracellular growth in the absence of IFNγ but suppressed IFNγ-mediated autophagy and growth restriction, indicating that the regulatory phenotype extends to function. The IFNγ-refractory phenotype was partly mediated by IL-27-signalling, establishing functional relevance for this downstream cytokine. These findings identify a novel macrophage-modulating function for the ESX-1 secretion system that may contribute to suppress the efficacy of adaptive immunity and provide mechanistic insight into the antagonistic cross talk between type I IFNs and IFNγ in mycobacterial infection.
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| 2. |
- Movert, Elin
(författare)
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Induction and functional role of type I interferon in bacterial infection of macrophages
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Infection represents an evolutionary arms race between pathogen and host. Thus, scientists find that pathogenic microbes have evolved elegant strategies to manipulate or avoid our immune system, allowing them to persist within the human population. This thesis is largely focused on how bacteria regulate and exploit the type I interferon (IFN) response in infected macrophages – a processes of central importance to cellular immunity and bacterial pathogenesis. More specifically, we have been interested in understanding how Streptococcus pyogenes and mycobacteria – representing evolutionarily distant pathogens causing acute and chronic infections, respectively – interact with macrophages to induce and functionally exploit the type I IFN response. Our studies have identified a specific streptococcal component, the surface M protein, and the mechanisms underlying induction of the type I IFN response in infected macrophages. In the case of mycobacterial infection, we provide new insight into the genetic requirements and mechanisms for ESX-1-mediated type I IFN induction, and describe a macrophage-modulating role for induced type I IFN that can be exploited by the bacteria to avoid being cleared by the immune system.
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| 3. |
- Movert, Elin, et al.
(författare)
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Streptococcal M protein promotes IL-10 production by cGAS-independent activation of the STING signaling pathway
- 2018
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7374 .- 1553-7366. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- From an evolutionary point of view a pathogen might benefit from regulating the inflammatory response, both in order to facilitate establishment of colonization and to avoid life-threatening host manifestations, such as septic shock. In agreement with this notion Streptococcus pyogenes exploits type I IFN-signaling to limit detrimental inflammation in infected mice, but the host-pathogen interactions and mechanisms responsible for induction of the type I IFN response have remained unknown. Here we used a macrophage infection model and report that S. pyogenes induces anti-inflammatory IL-10 in an M protein-dependent manner, a function that was mapped to the B- and C-repeat regions of the M5 protein. Intriguingly, IL-10 was produced downstream of type I IFN-signaling, and production of type I IFN occurred via M protein-dependent activation of the STING signaling pathway. Activation of STING was independent of the cytosolic double stranded DNA sensor cGAS, and infection did not induce detectable release into the cytosol of either mitochondrial, nuclear or bacterial DNA–indicating DNA-independent activation of the STING pathway in S. pyogenes infected macrophages. These findings provide mechanistic insight concerning how S. pyogenes induces the type I IFN response and identify a previously unrecognized macrophage-modulating role for the streptococcal M protein that may contribute to curb the inflammatory response to infection.
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| 4. |
- van Hensbergen, Vincent P., et al.
(författare)
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Streptococcal Lancefield polysaccharides are critical cell wall determinants for human Group IIA secreted phospholipase A2 to exert its bactericidal effects
- 2018
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 14:10, s. 1007348-1007348
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Tidskriftsartikel (refereegranskat)abstract
- Human Group IIA secreted phospholipase A2 (hGIIA) is an acute phase protein with bactericidal activity against Gram-positive bacteria. Infection models in hGIIA transgenic mice have suggested the importance of hGIIA as an innate defense mechanism against the human pathogens Group A Streptococcus (GAS) and Group B Streptococcus (GBS). Compared to other Gram-positive bacteria, GAS is remarkably resistant to hGIIA activity. To identify GAS resistance mechanisms, we exposed a highly saturated GAS M1 transposon library to recombinant hGIIA and compared relative mutant abundance with library input through transposon-sequencing (Tn-seq). Based on transposon prevalence in the output library, we identified nine genes, including dltA and lytR, conferring increased hGIIA susceptibility. In addition, seven genes conferred increased hGIIA resistance, which included two genes, gacH and gacI that are located within the Group A Carbohydrate (GAC) gene cluster. Using GAS 5448 wild-type and the isogenic gacI mutant and gacI-complemented strains, we demonstrate that loss of the GAC N-acetylglucosamine (GlcNAc) side chain in the ΔgacI mutant increases hGIIA resistance approximately 10-fold, a phenotype that is conserved across different GAS serotypes. Increased resistance is associated with delayed penetration of hGIIA through the cell wall. Correspondingly, loss of the Lancefield Group B Carbohydrate (GBC) rendered GBS significantly more resistant to hGIIA-mediated killing. This suggests that the streptococcal Lancefield antigens, which are critical determinants for streptococcal physiology and virulence, are required for the bactericidal enzyme hGIIA to exert its bactericidal function.
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